Prognostic disparities in young patients based on breast cancer subtype: A population-based study from the SEER database

Triple-negative breast cancer (TNBC) is associated with younger age and worse long-term survival. However, the characteristics and prognosis of different subtypes of breast cancer (BC) in young (<40 years) patients have not yet been elucidated. The present population-based study explored the clinical and pathological characteristics of young TNBC patients and investigated their long-term survival. We enrolled patients from the Surveillance, Epidemiology, and End Results database younger than 40 years of age with primary BC. Cases were defined as patients with TNBC (hormone receptor [HR]−/human epidermal growth factor receptor 2 [HER2]−), and controls were patients with other subtypes of BC (HR−/HER2+, HR+/HER2−, and HR+/HER2+). Demographic, pathological, and radiotherapy, chemotherapy, and surgery data were extracted and the overall survival was the primary endpoint. We enrolled 14,234 young patients with BC in the present study, of whom 2798 (19.7%) had TNBC and 11,436 (80.3%) had another BC subtype. A higher proportion of TNBC patients than non-TNBC patients had a more advanced tumor-node-metastasis stage (II–IV 80.5% vs 73.1%, P < .001), and smaller proportions underwent radiotherapy (50.0% vs 53.3%, P = .002) and surgery (91.8% vs 92.9%, P < .001). TNBC was associated with significantly lower 5-year survival rates than other subtypes among patients with regional node positivity (0, 1–3, 4–9, ≥10: 54.2% vs 57.7%, 44.2% vs 55.9%, 31.0% vs 52.0%, and 27.7% vs 38.8%, P < .001) and those with different lymph node ratios (low, intermediate, high: 50.9% vs 56.0%, 34.6% vs 53.6%, and 24.8% vs 44.8%, P < .001). Our research is the first to investigate the relevant characteristics of young TNBC patients in comparison with those of young non-TNBC patients based on the surveillance, epidemiology, and end results database. We found that young TNBC patients have a higher pathological stage and worse long-term survival than young patients with other BC subtypes. These findings have implications in identifying young patients with TNBC for aggressive therapy and further investigations should be performed to explore new multimodal treatments for such patients.


Introduction
Breast cancer (BC) is the most common form of cancer in women worldwide, and the prognosis is poor. [1] Cancer is caused by many changes within organisms and in the environment. [2] The DNA of the most vertebrates especially mammals is depleted in CpG dinucleotides. [3] The remaining CpGs clustering in DNA regions is generally referred to as CpG islands (CGIs). There has been growing interest in CGI because they are enriched in the promoters of genes [3] and by altering DNA methylation in CGIs, they play important roles in the regulation of gene expression and gene silencing in biological processes such as X-chromosome inactivation, imprinting, silencing of intragenomic parasites [4] and considerably, would help to discover the epigenetic causes of cancer, [5] hence the aim of this study is to evaluate clinical and pathological characteristics of BC patients with different gene expressions.
Triple-negative breast cancer (TNBC), which is estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2 (HER2)-negative, accounts for 15% to 20% of BC cases. [6] TNBC is associated with young age, advanced stage, and worse long-term survival compared to other subtypes. [7][8][9] Thike et al [10] analyzed 653 patients with TNBC and found worse disease-free survival and overall survival (OS) in young patients with TNBC compared to older patients with TNBC. Numerous other studies have reported similar results regarding the long-term prognosis in young patients with TNBC. [11,12] Although younger patients with BC are usually able to undergo more intensive therapy, better survival cannot be achieved because younger patients tend to have more aggressive disease. [13] It is particularly important to study clinical and pathological characteristics of young patients with different subtypes of BC for better treatments.
Lymph node (LN) metastases play a vital role in BC development, especially in TNBC. And LN assessment is an effective prognostic indicator in patients with BC. [14,15] The lymph node ratio (LNR), defined as the ratio of positive LNs to total excised LNs, has been shown to be a promising predictor for patients with BC. Moreover, some studies have shown that LNR is an independent factor for OS. [16,17] Although age as a prognostic factor has been assessed in BC, there are few studies revealing the characteristics of different subtypes of young BC patients. In the current population-based study, we sought to explore the clinical and pathological characteristics of young TNBC patients and investigate their long-term survival.

Patient screening
The present analysis selected data from the 18 registries of the surveillance, epidemiology, and end results (SEER) program. We enrolled BC patients diagnosed after 2010 since the HER2 receptor subtype was not available in the SEER database until 2010. The inclusion criteria were as follows: Female primary BC patients diagnosed at younger than 40 years; Unilateral invasive BC; Record of hormone receptor (HR) status, including estrogen receptor and progesterone receptor status, and HER2 receptor status; Complete clinical and pathological information, including age, race, marital status, 6 th American Joint Committee on Cancer tumor stage, [18] and number of positive regional lymph nodes; and OS of more than 3 months. Patients who did not meet these criteria or had incomplete data were excluded from the study. This study was approved by the Ethics Committee of Xiamen Humanity Hospital Fujian Medical University.

Study design
The study population consisted of young patients with BC diagnosed between January 2010 and December 2017. This  study used a case-control design to investigate the clinical and pathological outcomes of young patients with TNBC. Cases were defined as patients with TNBC (HR−/HER2−). Controls included patients with non-TNBC (HR−/HER2+, HR+/HER2−, and HR+/HER2+). We extracted demographic, pathological, and radiotherapy, chemotherapy, and surgery data. The LNR was calculated as the number of positive LNs divided by the number of resected LNs. We define a higher pathological state as a worse differentiation (grade III-IV) and more advanced tumor-node-metastasis (TNM) stage (II-IV). [12] Patients were divided into low-risk (≤0.20), intermediate-risk (0.20-0.65), and high-risk (>0.65) LNR groups. OS was the primary endpoint.

Statistical analyses
SPSS 22.0 statistical software was used for statistical analysis. [19] The demographic, pathological, and radiotherapy, chemotherapy, and surgery data were compared using the chisquare test. Subgroup analyses were performed to investigate  the characteristics of TNBC and non-TNBC patients associated with OS. OS rates were calculated using the Kaplan-Meier method. Prognostic factors associated with survival were estimated by univariate and multivariable Cox proportional hazard models. To avoid confounding bias (age, race, and marital status), propensity score matching was performed using a small caliper of 0.1. Statistical significance was set at P < .05.

Survival analysis
Univariate and multivariate analyses confirmed that unmarried status, TNBC, higher TNM stage, higher grade, more positive regional nodes, and lack of surgery were associated with a worse prognosis (Table 2). To better understand the impact of BC subtype on OS, a subgroup analysis was performed. A forest plot revealed that TNBC was related to an increased risk of death in all groups except the American Indian/Alaska native and grade IV groups (Fig. 3). We compared the OS between the TNBC and non-TNBC groups based on positive regional nodes and LNR. Propensity score matching was used to avoid baseline bias. Significant differences in 5-year survival rates were found in patients with and without TNBC in the regional node-positive group (0, . Survival analysis after propensity score matching also demonstrated that patients with TNBC had worse prognosis (P < .001).

Discussion
TNBC is usually diagnosed at a young age. [7,8,20,21] Numerous studies have demonstrated that BC patients younger than 40 years have a distinct disease with consistently poor long-term prognosis. [22][23][24][25][26] However, there is little evidence regarding the clinical and pathological characteristics of young (<40 years) TNBC patients in comparison with those of non-TNBC patients.
To the best of our knowledge, the present study is the first to investigate the relevant characteristics of young TNBC patients in comparison with those of young non-TNBC patients based on the SEER database. Our study revealed a markedly higher pathological stage and less relevant anticancer treatments, except chemotherapy, in TNBC patients, which are similar to the results of a previous study. [12,27,28] Furthermore, multivariate and subgroup analyses revealed that TNBC was associated with a worse prognosis. Moreover, TNBC was associated with a worse OS than non-TNBC in all LNR groups. Young patients with TNBC are more likely to have a higher pathological stage and worse long-term survival. This study involved young BC patients, 42.9% of TNBC patients had LN metastasis, which is higher than the rate reported in a previous study of TNBC. [29] Young patients are more likely to have aggressive disease, which may be the result of a higher rate of BRCA mutations. [30,31] However, unlike previous studies, our investigation found that fewer patients with TNBC had positive regional nodes than patients with other BC subtypes (42.9% vs 53.6%, P < .001). Additional chemotherapy in patients with TNBC may reduce the rate of positive LNs. Interestingly, TNBC patients were less likely than non-TNBC patients to undergo surgery, despite a higher rate of chemotherapy. It is not beneficial for patients in terms of the tumor loads. [32] Because the patients enrolled in our study were young, we focused on the 5-year survival rate instead of the short-term prognosis. We found that TNBC patients had worse 5-year survival than non-TNBC patients among young BC patients, and the analysis after propensity score matching confirmed this finding (P < .001). Moreover, multivariate and subgroup analyses identified that TNBC was associated with an increased overall risk of death among young patients compared with non-TNBC. Although chemotherapy is now acknowledged as a systemic treatment for TNBC patients, we observed a limited effect. This may be due to a lack of molecular targets in these patients. [12] Steward et al [33] demonstrated that radiation therapy after lumpectomy is associated with better prognosis in patients with TNBC. Other studies have also confirmed that postmastectomy radiation therapy increases disease-free survival in patients with T1-T2 disease. [34] However, the single treatment has limited effect on the long-term prognosis due to local or distant residual lesions. [35] Our survival analysis also showed that LN metastasis decreased survival, which indicates that reduced residual tumor load plays a vital role in young patients with BC. Therefore, multimodality treatments should be encouraged, including chemotherapy, radiotherapy, and surgery, especially in young patients with TNBC. Further larger scale studies are needed for individualized therapies in such patients.
This study has some limitations. First, although propensity score matching was used to avoid baseline bias, treatments such as chemotherapy, radiotherapy, and surgery still influenced long-term survival. Second, some variables were not included, including chemotherapy regimen, surgical treatment, and gene mutations. Last, the lack of further classification of non-TNBC is not conductive to the expansion of research results.

Conclusion
Our results suggest that young patients with TNBC are more likely to have a higher pathological stage than other BC subtypes, which may lead to a worse long-term survival. As young patients tend to have better survival expectations, these findings also have implications in identifying young patients with TNBC for aggressive therapy. Large RCTs are needed to investigate better treatments and improve follow up in these patients.